Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV17DY2)

• DOT Name: Src-like-adapter (SLA)
• Synonyms: Src-like-adapter protein 1; SLAP-1; hSLAP
• Gene Name: SLA
• Related Disease:
  Graves disease
  Hepatitis B virus infection
  Vitiligo
• UniProt ID: SLAP1_HUMAN
• PDB ID: 2CUD
• Pfam ID: PF00017 ; PF00018
• Sequence:
  MGNSMKSTPAPAERPLPNPEGLDSDFLAVLSDYPSPDISPPIFRRGEKLRVISDEGGWWK
  AISLSTGRESYIPGICVARVYHGWLFEGLGRDKAEELLQLPDTKVGSFMIRESETKKGFY
  SLSVRHRQVKHYRIFRLPNNWYYISPRLTFQCLEDLVNHYSEVADGLCCVLTTPCLTQST
  AAPAVRASSSPVTLRQKTVDWRRVSRLQEDPEGTENPLGVDESLFSYGLRESIASYLSLT
  SEDNTSFDRKKKSISLMYGGSKRKSSFFSSPPYFED
• Function: Adapter protein, which negatively regulates T-cell receptor (TCR) signaling. Inhibits T-cell antigen-receptor induced activation of nuclear factor of activated T-cells. Involved in the negative regulation of positive selection and mitosis of T-cells. May act by linking signaling proteins such as ZAP70 with CBL, leading to a CBL dependent degradation of signaling proteins.
• Tissue Specificity: Expressed in lung and fetal brain. Weakly expressed in heart, adult brain, placenta, liver, skeletal muscle, kidney and pancreas.
• Reactome Pathway: Negative regulation of FLT3 (R-HSA-9706369)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Graves disease	DISU4KOQ	Strong	Genetic Variation	[1]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[2]
Vitiligo	DISR05SL	Strong	Biomarker	[3]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Src-like-adapter (SLA).	[4]

12 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Src-like-adapter (SLA).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Src-like-adapter (SLA).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Src-like-adapter (SLA).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Src-like-adapter (SLA).	[8]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Src-like-adapter (SLA).	[9]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Src-like-adapter (SLA).	[10]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Src-like-adapter (SLA).	[11]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Src-like-adapter (SLA).	[12]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of Src-like-adapter (SLA).	[10]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Src-like-adapter (SLA).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Src-like-adapter (SLA).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Src-like-adapter (SLA).	[14]

References

• [1] Robust evidence for five new Graves' disease risk loci from a staged genome-wide association analysis.Hum Mol Genet. 2013 Aug 15;22(16):3347-62. doi: 10.1093/hmg/ddt183. Epub 2013 Apr 23.
• [2] Sulfated archaeol glycolipids: Comparison with other immunological adjuvants in mice.PLoS One. 2018 Dec 4;13(12):e0208067. doi: 10.1371/journal.pone.0208067. eCollection 2018.
• [3] Genome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo.Nat Genet. 2012 May 6;44(6):676-80. doi: 10.1038/ng.2272.
• [4] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [5] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [6] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [7] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [8] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [11] Gene expression profile of human lymphoid CEM cells sensitive and resistant to glucocorticoid-evoked apoptosis. Genomics. 2003 Jun;81(6):543-55.
• [12] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [13] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [14] Transcriptomic?pathway?and?benchmark dose analysis of Bisphenol A, Bisphenol S, Bisphenol F, and 3,3',5,5'-Tetrabromobisphenol A in H9 human embryonic stem cells. Toxicol In Vitro. 2021 Apr;72:105097. doi: 10.1016/j.tiv.2021.105097. Epub 2021 Jan 18.